The PIM kinases are serine/threonine kinase which play essential role in the regulation of cell cycle, apoptosis, metabolism, autophagy, drug resistance and targeted therapy. PIM-1 specially overexpressed in hematologic and solid tumors. In the present study, we have utilized atom-based 3D-QSAR method to analyze the structural aspects on a series of thiazolidine-2,4-dione derivatives as potent inhibitors of PIM-1 kinase. These interpretated results used in the synthesis of novel thiazolidine-2,4-diones derivatives. The reported experimental results by Dakin, Xia and co-workers on the inhibition of PIM-1 kinase by the thiazolidine-2,4-dione derivatives were correlated using robust 3D-QSAR as well as docking methods. This approach led us to short-list the most active PIM-1 derivatives such as compounds 29, 33, 35 and 18 with the incorporation of more than one structural feature in a single molecule. The validation of experimental results by docking study give the idea about further development of the most potent anticancer compounds as PIM-1 kinase inhibitors.